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Anti-inflammatory effects of intravenous immunoglobulin (IVIg) : what are the mechanisms of action?

Sordé, Laetitia. Anti-inflammatory effects of intravenous immunoglobulin (IVIg) : what are the mechanisms of action? 2016, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_11719

Abstract

Intravenous immunoglobulin (IVIg) is a pool of plasma polyclonal IgG derived from thousands of healthy donors. Initially employed as a replacement therapy in patients suffering from immunodeficiency, in the 80’s, IVIg was shown to surprisingly ameliorate immune thrombocytopenia by some immunosuppressive properties. Since then, the use of IVIg has rocketed in the treatment of a wide range of autoimmune and severe inflammatory diseases. It is commonly administered in the clinic at very high doses (1 to 4 g/kg) in order to achieve anti-inflammatory effects. However, its mechanisms of action remain poorly understood. This PhD project aimed at investigating whether IVIg has a direct impact on immune cell populations in vivo in mice, characterizing the antibody response upon IVIg treatment and exploring how these different effects could explain the immunomodulatory properties of IVIg.
By using an OVA-immunization mouse model, we demonstrated that IVIg was able to significantly reduce the OVA-specific antibody response in a dose-dependent manner, as observed in the clinic. Intriguingly, IVIg injection led to B- and T-cell expansion in the corresponding draining lymph nodes, as translated by their considerable increase in weight. IVIg augmented the number of CD69+ activated T cells but didn’t promote Tregs activation. Notably, it induced a marked stimulation of B cells as shown by the up-regulation of the co-stimulatory molecules CD86 and CD83, as well as the early activation marker CD69. More strikingly, IVIg administration in mice resulted in the formation of large and numerous germinal centers in lymphoid organs. Analysis of the bone marrow revealed that less mature B cells were re-circulating, suggesting that they get trapped in the lymph nodes. In addition, the number of total IgG immunoglobulin-secreting cells was greatly enhanced upon IVIg treatment, whereas the ratio of OVA-IgG antibodies secreting cells was diminished. All these effects were dependent on the presence of adjuvant and could not be reproduced by the administration of a human monoclonal antibody at the same high dose. These data collectively point to the direction that IVIg triggers immune activation, although the resulting outcome is the inhibition of the OVA-antibody response. This was confirmed by further data showing that IVIg raised an IVIg specific antibody response in mice, mainly targeted towards its variable regions. This suggests that IVIg directly activates B cells after binding to the BCR most probably via an anti-idiotypic interaction. Very interestingly, mouse immunization with NP-Ficoll revealed that IVIg was not able to significantly downregulate antibodies against a thymus-independent antigen, implying a competition at the T cell level.
Research over the past decades has emphasized the role of IVIg in promoting anti-inflammatory effects, e.g. activation of Tregs, induction of inhibitory FcγRIIB expression, saturation of FcRn, or modulation of co-stimulatory molecules expression on DCs. In contrast, our data indicate an immediate and massive immune reaction against IVIg in vivo. We propose that the many different variable sequences present in IVIg introduce a multitude of new foreign epitopes re-directing the immune system. Antigenic competition of IVIg with the response against OVA may occur at different stages in the immune reaction. Driven by the high diversity of T- and B cell epitopes, competition may occur during i) scanning of peptides by T cells on dendritic cells ii) priming of B cells by cognate T helper cells at the B/T cell border iii) priming of B cells by cognate T follicular helper cells within the germinal center.
Therefore, we suggest that rather than acting as an active anti-inflammatory component, IVIg interferes with establishing an efficient immune response against a specific antigen via a huge diversity of epitopes re-directing the immune system towards a massive immune response against IVIg.
Advisors:Palmer, Ed and Karle, Anette and De Libero, Gennaro
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Transplantation Immunology and Nephrology (Palmer/Steiger)
Item Type:Thesis
Thesis no:11719
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (164 Seiten)
Language:English
Identification Number:
Last Modified:04 Jul 2016 09:10
Deposited On:04 Jul 2016 09:07

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